Using two different cell-mediated respones (secondary lymphocyte proliferative responses and secondary cell-mediated cytotoxicity) we have continued to probe the complexities of the alloantigenic differences between normal human donors. Development of SB2-specific cytotoxic T cell (CTL) clones has facilitated detailed analysis of SB-region determinnants. Seventy anti-Ia monoclonal antibodies have been studied systematically for their ability to inhibit SB-specific cell-mediated cytotoxicity. Both inhibition and enhancement have been seen, which suggests a complex relationship between the epitope recognized by antibody and that recognized by T cells. Binding and inhibition studies indicate that one of the monoclonal antibodies studies identifies a new SB-related gene product. Analysis of the specificity of a panel of 10 SB-specific CTL clones demonstrates homogeneity of the SB2 phenotype in populations of normal Caucasians but reveals striking diversity of SB2-specific T cell recognition on HLA-deletion mutant cell lines. Some differences between mutant cell lines is apparently controlled by a new HLA gene which is being identified. In addition, one CTL clone detects a variation between donors in the population which is consistent with structural heterogeneity of SB2-related alleles. Studies of human histocompatibility antigens are continuing but have been hampered by technical difficulties.